chr7-124827288-G-T

Variant names:

• chr7-124827288-G-T
• rs768610116
• NM_015450.3:c.1612C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015450.3(POT1):​c.1612C>A​(p.Leu538Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,438,720 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L538F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POT1 NM_015450.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50
• Publications: 0 publications found

Genes affected

POT1 (HGNC:17284): (protection of telomeres 1) This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

POT1 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tumor predisposition syndrome 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• glioma susceptibility 9

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• thyroid gland carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• cerebroretinal microangiopathy with calcifications and cysts 3

  Inheritance: AR Classification: LIMITED Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015450.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	NM_015450.3	MANE Select	c.1612C>A	p.Leu538Ile	missense	Exon 17 of 19	NP_056265.2
	POT1	NM_001042594.2		c.1219C>A	p.Leu407Ile	missense	Exon 16 of 18	NP_001036059.1
	POT1	NR_003102.2		n.2175C>A		non_coding_transcript_exon	Exon 18 of 20

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POT1	ENST00000357628.8	TSL:2 MANE Select	c.1612C>A	p.Leu538Ile	missense	Exon 17 of 19	ENSP00000350249.3
	POT1	ENST00000607932.5	TSL:1	n.1523C>A		non_coding_transcript_exon	Exon 12 of 14	ENSP00000476506.1
	POT1	ENST00000608057.5	TSL:1	n.*709C>A		non_coding_transcript_exon	Exon 14 of 16	ENSP00000476371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438720 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 716376

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32818

American (AMR) AF: 0.00 AC: 0 AN: 44192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39216

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094076

Other (OTH) AF: 0.00 AC: 0 AN: 59580

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.0066	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.60
MutPred		0.39		Gain of sheet (P = 0.1451)
MVP		0.42
MPC		0.34
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.36
gMVP		0.60
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768610116; hg19: chr7-124467342;